Randomized Controlled Trial

4/21/2020 Randomized controlled trial - Wikipedia
Randomized controlled trial

A randomized controlled trial (or
[2]
randomized control trial; RCT) is a type
of scientific (often medical) experiment that aims
to reduce certain sources of bias when testing the
effectiveness of new treatments; this is
accomplished by randomly allocating subjects to
two or more groups, treating them differently,
and then comparing them with respect to a
measured response. One group—the
experimental group—has the intervention being
assessed, while the other—usually called the
control group—has an alternative condition, such
as a placebo or no intervention. The groups are
followed under conditions of the trial design to
see how effective the experimental intervention
was.[3] Treatment efficacy is assessed in
comparison to the control. There may be more
than one treatment group or more than one
control group. Flowchart of four phases (enrollment, allocation,
intervention, follow-up, and data analysis) of a parallel
The trial may be blinded, in which information randomized trial of two groups (in a controlled trial, one
which may influence the participants is withheld of the interventions serves as the control), modified
until after the experiment is complete. A blind from the CONSORT (Consolidated Standards of
can be imposed on any participant of an Reporting Trials) 2010 Statement[1]
experiment, including subjects, researchers,
technicians, data analysts, and evaluators. Good
blinding may reduce or eliminate some sources of experimental bias.
The randomness in the assignment of subjects to groups reduces selection bias and allocation bias,
balancing both known and unknown prognostic factors, in the assignment of treatments.[4] Blinding
reduces other forms of experimenter and subject biases.
A well-blinded RCT is often considered the gold standard for clinical trials. Blinded RCTs are
commonly used to test the efficacy of medical interventions and may additionally provide
information about adverse effects, such as drug reactions.
The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term
omits mention of controls and can therefore describe studies that compare multiple treatment
groups with each other in the absence of a control group.[5] Similarly, the initialism is sometimes
expanded as "randomized clinical trial" or "randomized comparative trial", leading to
ambiguity in the scientific literature.[6][7] Not all randomized clinical trials are randomized
controlled trials (and some of them could never be, as in cases where controls would be impractical
or unethical to institute). The term randomized controlled clinical trial is an alternative term
used in clinical research;[8] however, RCTs are also employed in other research areas, including
many of the social sciences.
Contents
https://en.wikipedia.org/wiki/Randomized_controlled_trial 1/24
History
Ethics
Trial registration
Classifications
By study design
By outcome of interest (efficacy vs. effectiveness)
By hypothesis (superiority vs. noninferiority vs. equivalence)
Randomization
Procedures
Allocation concealment
Sample size
Blinding
Analysis of data
Reporting of results
Relative importance and observational studies
Interpretation of statistical results
Peer review
Advantages
Disadvantages
Time and costs
Conflict of interest dangers
Ethics
In social science
Transport science
International development
Criminology
Education
Criticism
See also
References
Further reading
External links
History
The first reported clinical trial was conducted by James Lind in 1747 to identify treatment for
scurvy.[9] Randomized experiments appeared in psychology, where they were introduced by Charles
Sanders Peirce and Joseph Jastrow in the 1880s,[10] and in education.[11][12][13] Later, in the early
20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman[14] and Ronald
A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.[15]
The first published RCT in medicine appeared in the 1948 paper entitled "Streptomycin treatment of
pulmonary tuberculosis", which described a Medical Research Council investigation.[16][17][18] One
of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the
modern RCT.[19]
By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in
medicine.[20] As of 2004, more than 150,000 RCTs were in the Cochrane Library.[19] To improve the
reporting of RCTs in the medical literature, an international group of scientists and editors
published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and
2010, and these have become widely accepted.[1][4] Randomization is the process of assigning trial
subjects to treatment or control groups using an element of chance to determine the assignments in
order to reduce the bias.
Ethics
Although the principle of clinical equipoise ("genuine uncertainty within the expert medical
community... about the preferred treatment") common to clinical trials[21] has been applied to RCTs,
the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is
insufficient to justify RCTs.[22] For another, "collective equipoise" can conflict with a lack of personal
equipoise (e.g., a personal belief that an intervention is effective).[23] Finally, Zelen's design, which
has been used for some RCTs, randomizes subjects before they provide informed consent, which may
be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic
trials."[24][25]
Although subjects almost always provide informed consent for their participation in an RCT, studies
since 1982 have documented that RCT subjects may believe that they are certain to receive treatment
that is best for them personally; that is, they do not understand the difference between research and
treatment.[26][27] Further research is necessary to determine the prevalence of and ways to address
this "therapeutic misconception".[27]
The RCT method variations may also create cultural effects that have not been well understood.[28]
For example, patients with terminal illness may join trials in the hope of being cured, even when
treatments are unlikely to be successful.
Trial registration
In 2004, the International Committee of Medical Journal Editors (http://www.icmje.org/) (ICMJE)

announced that all trials starting enrolment after July 1, 2005 must be registered prior to
consideration for publication in one of the 12 member journals of the committee.[29] However, trial
registration may still occur late or not at all.[30][31] Medical journals have been slow in adapting
policies requiring mandatory clinical trial registration as a prerequisite for publication.[32]
Classifications
By study design
One way to classify RCTs is by study design. From most to least common in the healthcare literature,
the major categories of RCT study designs are:[33]
Parallel-group – each participant is randomly assigned to a group, and all the participants in the
group receive (or do not receive) an intervention.
Crossover – over time, each participant receives (or does not receive) an intervention in a
random sequence.[34][35]
Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected to
receive (or not receive) an intervention.
Factorial – each participant is randomly assigned to a group that receives a particular

combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin Y,
group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group
4 receives placebo X and placebo Y).
An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were
parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were
factorial.[33]
By outcome of interest (efficacy vs. effectiveness)
RCTs can be classified as "explanatory" or "pragmatic."[36] Explanatory RCTs test efficacy in a

research setting with highly selected participants and under highly controlled conditions.[36] In
contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected
participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about
practice."[36]
By hypothesis (superiority vs. noninferiority vs. equivalence)
Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and
"equivalence trials", which differ in methodology and reporting.[37] Most RCTs are superiority trials,
in which one intervention is hypothesized to be superior to another in a statistically significant
way.[37] Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than
a reference treatment."[37] Other RCTs are equivalence trials in which the hypothesis is that two
interventions are indistinguishable from each other.[37]
Randomization
The advantages of proper randomization in RCTs include:[38]
"It eliminates bias in treatment assignment," specifically selection bias and confounding.
"It facilitates blinding (masking) of the identity of treatments from investigators, participants, and
assessors."
"It permits the use of probability theory to express the likelihood that any difference in outcome
between treatment groups merely indicates chance."
There are two processes involved in randomizing patients to different interventions. First is choosing
a randomization procedure to generate an unpredictable sequence of allocations; this may be a
simple random assignment of patients to any of the groups at equal probabilities, may be
"restricted", or may be "adaptive." A second and more practical issue is allocation concealment,
which refers to the stringent precautions taken to ensure that the group assignment of patients are
not revealed prior to definitively allocating them to their respective groups. Non-random
"systematic" methods of group assignment, such as alternating subjects between one group and the
other, can cause "limitless contamination possibilities" and can cause a breach of allocation
concealment.[39]
However empirical evidence that adequate randomization changes outcomes relative to inadequate
randomization has been difficult to detect.[40]
Procedures
The treatment allocation is the desired proportion of patients in each treatment arm.
An ideal randomization procedure would achieve the following goals:[41]
Maximize statistical power, especially in subgroup analyses. Generally, equal group sizes
maximize statistical power, however, unequal groups sizes may be more powerful for some
analyses (e.g., multiple comparisons of placebo versus several doses using Dunnett's
procedure[42] ), and are sometimes desired for non-analytic reasons (e.g., patients maybe more
motivated to enroll if there is a higher chance of getting the test treatment, or regulatory agencies
may require a minimum number of patients exposed to treatment).[43]
Minimize selection bias. This may occur if investigators can consciously or unconsciously
preferentially enroll patients between treatment arms. A good randomization procedure will be
unpredictable so that investigators cannot guess the next subject's group assignment based on
prior treatment assignments. The risk of selection bias is highest when previous treatment
assignments are known (as in unblinded studies) or can be guessed (perhaps if a drug has
distinctive side effects).
Minimize allocation bias (or confounding). This may occur when covariates that affect the
outcome are not equally distributed between treatment groups, and the treatment effect is
confounded with the effect of the covariates (i.e., an "accidental bias"[38][44]). If the randomization
procedure causes an imbalance in covariates related to the outcome across groups, estimates of
effect may be biased if not adjusted for the covariates (which may be unmeasured and therefore
impossible to adjust for).
However, no single randomization procedure meets those goals in every circumstance, so

researchers must select a procedure for a given study based on its advantages and disadvantages.
Simple
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing."[38] Also
known as "complete" or "unrestricted" randomization, it is robust against both selection and
accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small
RCTs. It is therefore recommended only for RCTs with over 200 subjects.[45]
Restricted
To balance group sizes in smaller RCTs, some form of "restricted" randomization is

recommended.[45] The major types of restricted randomization used in RCTs are:
Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio"

(number of subjects in one group versus the other group) are specified, and subjects are
allocated randomly within each block.[39] For example, a block size of 6 and an allocation ratio of
2:1 would lead to random assignment of 4 subjects to one group and 2 to the other. This type of
randomization can be combined with "stratified randomization", for example by center in a
multicenter trial, to "ensure good balance of participant characteristics in each group."[4] A
special case of permuted-block randomization is random allocation, in which the entire sample is
treated as one block.[39] The major disadvantage of permuted-block randomization is that even if
the block sizes are large and randomly varied, the procedure can lead to selection bias.[41]
Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs
requires stratification by blocks.[45]
Adaptive biased-coin randomization methods (of which urn randomization is the most widely
known type): In these relatively uncommon methods, the probability of being assigned to a group
decreases if the group is overrepresented and increases if the group is underrepresented.[39]
The methods are thought to be less affected by selection bias than permuted-block
randomization.[45]
Adaptive
At least two types of "adaptive" randomization procedures have been used in RCTs, but much less
frequently than simple or restricted randomization:
Covariate-adaptive randomization, of which one type is minimization: The probability of being

assigned to a group varies in order to minimize "covariate imbalance."[45] Minimization is
reported to have "supporters and detractors"[39] because only the first subject's group
assignment is truly chosen at random, the method does not necessarily eliminate bias on
unknown factors.[4]
Response-adaptive randomization, also known as outcome-adaptive randomization: The
probability of being assigned to a group increases if the responses of the prior patients in the
group were favorable.[45] Although arguments have been made that this approach is more
ethical than other types of randomization when the probability that a treatment is effective or
ineffective increases during the course of an RCT, ethicists have not yet studied the approach in
detail.[46]
Allocation concealment
"Allocation concealment" (defined as "the procedure for protecting the randomization process so
that the treatment to be allocated is not known before the patient is entered into the study") is
important in RCTs.[47] In practice, clinical investigators in RCTs often find it difficult to maintain
impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking
offices to determine group assignments in order to dictate the assignment of their next patient.[39]
Such practices introduce selection bias and confounders (both of which should be minimized by
randomization), possibly distorting the results of the study.[39] Adequate allocation concealment
should defeat patients and investigators from discovering treatment allocation once a study is
underway and after the study has concluded. Treatment related side-effects or adverse events may be
specific enough to reveal allocation to investigators or patients thereby introducing bias or
influencing any subjective parameters collected by investigators or requested from subjects.
Some standard methods of ensuring allocation concealment include sequentially numbered, opaque,
sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization;
and central randomization.[39] It is recommended that allocation concealment methods be included
in an RCT's protocol, and that the allocation concealment methods should be reported in detail in a
publication of an RCT's results; however, a 2005 study determined that most RCTs have unclear
allocation concealment in their protocols, in their publications, or both.[48] On the other hand, a
2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear
allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were
subjective as opposed to objective.[49]
Sample size
The number of treatment units (subjects or groups of subjects) assigned to control and treatment
groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment
units in either group may be insufficient for rejecting the null hypothesis in the respective statistical
test. The failure to reject the null hypothesis would imply that the treatment shows no statistically
significant effect on the treated in a given test. But as the sample size increases, the same RCT may
be able to demonstrate a significant effect of the treatment, even if this effect is small.[50]
Blinding
An RCT may be blinded, (also called "masked") by "procedures that prevent study participants,
caregivers, or outcome assessors from knowing which intervention was received."[49] Unlike
allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for
example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g.,
physical therapy), participants cannot be blinded to the intervention.
Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind";

however, in 2001 and 2006 two studies showed that these terms have different meanings for
different people.[51][52] The 2010 CONSORT Statement specifies that authors and editors should not
use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT
should discuss "If done, who was blinded after assignment to interventions (for example,
participants, care providers, those assessing outcomes) and how."[4]
RCTs without blinding are referred to as "unblinded",[53] "open",[54] or (if the intervention is a
medication) "open-label".[55] In 2008 a study concluded that the results of unblinded RCTs tended
to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to
objective;[49] for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists
(but not the blinded neurologists) felt that the treatments were beneficial.[56] In pragmatic RCTs,
although the participants and providers are often unblinded, it is "still desirable and often possible to
blind the assessor or obtain an objective source of data for evaluation of outcomes."[36]
Analysis of data
The types of statistical methods used in RCTs depend on the characteristics of the data and include:
For dichotomous (binary) outcome data, logistic regression (e.g., to predict sustained virological
response after receipt of peginterferon alfa-2a for hepatitis C[57]) and other methods can be
used.
For continuous outcome data, analysis of covariance (e.g., for changes in blood lipid levels after
receipt of atorvastatin after acute coronary syndrome[58]) tests the effects of predictor variables.
For time-to-event outcome data that may be censored, survival analysis (e.g., Kaplan–Meier
estimators and Cox proportional hazards models for time to coronary heart disease after receipt
of hormone replacement therapy in menopause[59]) is appropriate.
Regardless of the statistical methods used, important considerations in the analysis of RCT data
include:
Whether an RCT should be stopped early due to interim results. For example, RCTs may be
stopped early if an intervention produces "larger than expected benefit or harm", or if
"investigators find evidence of no important difference between experimental and control
interventions."[4]
The extent to which the groups can be analyzed exactly as they existed upon randomization (i.e.,
whether a so-called "intention-to-treat analysis" is used). A "pure" intention-to-treat analysis is
"possible only when complete outcome data are available" for all randomized subjects;[60] when
some outcome data are missing, options include analyzing only cases with known outcomes and
using imputed data.[4]

Nevertheless, the more that analyses can include all participants in the
groups to which they were randomized, the less bias that an RCT will be subject to.[4]
Whether subgroup analysis should be performed. These are "often discouraged" because
multiple comparisons may produce false positive findings that cannot be confirmed by other
studies.[4]
Reporting of results
The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for
reporting RCTs."[61] The CONSORT 2010 checklist contains 25 items (many with sub-items)
focusing on "individually randomised, two group, parallel trials" which are the most common type of
RCT.[1]
For other RCT study designs, "CONSORT extensions" have been published, some examples are:
Consort 2010 Statement: Extension to Cluster Randomised Trials[62]

Consort 2010 Statement: Non-Pharmacologic Treatment Interventions[63][64]
Relative importance and observational studies
Two studies published in The New England Journal of Medicine in 2000 found that observational
studies and RCTs overall produced similar results.[65][66] The authors of the 2000 findings
questioned the belief that "observational studies should not be used for defining evidence-based
medical care" and that RCTs' results are "evidence of the highest grade."[65][66] However, a 2001
study published in Journal of the American Medical Association concluded that "discrepancies
beyond chance do occur and differences in estimated magnitude of treatment effect are very
common" between observational studies and RCTs.[67]
Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types
of studies:
If study designs are ranked by their potential for new discoveries, then anecdotal evidence would
be at the top of the list, followed by observational studies, followed by RCTs.[68]
RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the
expected stable or progressively worse natural course of the condition treated.[69][70] One
example is combination chemotherapy including cisplatin for metastatic testicular cancer, which
increased the cure rate from 5% to 60% in a 1977 non-randomized study.[70][71]
Interpretation of statistical results
Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false
negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the
probability that the RCT will falsely find two equally effective treatments significantly different.[72]
Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of
many "negative" RCTs were too small to make definitive conclusions about the negative results,[73]
by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample
size calculations.[74]
Peer review
Peer review of results is an important part of the scientific method. Reviewers examine the study
results for potential problems with design that could lead to unreliable results (for example by
creating a systematic bias), evaluate the study in the context of related studies and other evidence,
and evaluate whether the study can be reasonably considered to have proven its conclusions. To
underscore the need for peer review and the danger of over-generalizing conclusions, two Boston-
area medical researchers performed a randomized controlled trial in which they randomly assigned
either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a
helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to
empty backpacks. The key context that limited the general applicability of this conclusion was that
the aircraft were parked on the ground, and participants had only jumped about two feet.[75]
Advantages
RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence
that influences healthcare policy and practice because RCTs reduce spurious causality and bias.
Results of RCTs may be combined in systematic reviews which are increasingly being used in the
conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or
systematic reviews of RCTs to be the highest-quality evidence available are:
As of 1998, the National Health and Medical Research Council of Australia designated "Level I"
evidence as that "obtained from a systematic review of all relevant randomised controlled trials"
and "Level II" evidence as that "obtained from at least one properly designed randomised
controlled trial."[76]
Since at least 2001, in making clinical practice guideline recommendations the United States
Preventive Services Task Force has considered both a study's design and its internal validity as
indicators of its quality.[77] It has recognized "evidence obtained from at least one properly
randomized controlled trial" with good internal validity (i.e., a rating of "I-good") as the highest
quality evidence available to it.[77]
The GRADE Working Group concluded in 2008 that "randomised trials without important
limitations constitute high quality evidence."[78]
For issues involving "Therapy/Prevention, Aetiology/Harm", the Oxford Centre for Evidence-
based Medicine as of 2011 defined "Level 1a" evidence as a systematic review of RCTs that are
consistent with each other, and "Level 1b" evidence as an "individual RCT (with narrow
Confidence Interval)."[79]
Notable RCTs with unexpected results that contributed to changes in clinical practice include:
After Food and Drug Administration approval, the antiarrhythmic agents flecainide and encainide
came to market in 1986 and 1987 respectively.[80] The non-randomized studies concerning the
drugs were characterized as "glowing",[81] and their sales increased to a combined total of
approximately 165,000 prescriptions per month in early 1989.[80] In that year, however, a
preliminary report of an RCT concluded that the two drugs increased mortality.[82] Sales of the
drugs then decreased.[80]
Prior to 2002, based on observational studies, it was routine for physicians to prescribe hormone
replacement therapy for post-menopausal women to prevent myocardial infarction.[81] In 2002
and 2004, however, published RCTs from the Women's Health Initiative claimed that women
taking hormone replacement therapy with estrogen plus progestin had a higher rate of
myocardial infarctions than women on a placebo, and that estrogen-only hormone replacement
therapy caused no reduction in the incidence of coronary heart disease.[59][83] Possible
explanations for the discrepancy between the observational studies and the RCTs involved
differences in methodology, in the hormone regimens used, and in the populations studied.[84][85]
The use of hormone replacement therapy decreased after publication of the RCTs.[86]
Disadvantages
Many papers discuss the disadvantages of RCTs.[69][87][88] Among the most frequently cited
drawbacks are:
Time and costs
RCTs can be expensive;[88] one study found 28 Phase III RCTs funded by the National Institute of
Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million,[89] for a mean
cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that
the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times
the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the
prevailing mean per capita gross domestic product.[89]
The conduct of an RCT takes several years until being published, thus data is restricted from the
medical community for long years and may be of less relevance at time of publication.[90]
It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some
interventions.[69][88]
Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome)
and uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with
extremely large sample sizes and may, therefore, best be assessed by observational studies.[69]
Due to the costs of running RCTs, these usually only inspect one variable or very few variables, rarely
reflecting the full picture of a complicated medical situation; whereas the case report, for example,
can detail many aspects of the patient's medical situation (e.g. patient history, physical examination,
diagnosis, psychosocial aspects, follow up).[90]
Conflict of interest dangers
A 2011 study done to disclose possible conflicts of interests in underlying research studies used for
medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies
underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general
medicine journals; 15 from specialty medicine journals, and 3 from the Cochrane Database of
Systematic Reviews. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled
trials (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of
the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing
industry financial ties with one or more authors. The information was, however, seldom reflected in
the meta-analyses. Only two (7%) reported RCT funding sources and none reported RCT author-
industry ties. The authors concluded "without acknowledgment of COI due to industry funding or
author industry financial ties from RCTs included in meta-analyses, readers' understanding and
appraisal of the evidence from the meta-analysis may be compromised."[91]
Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry)
as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found
four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all
the articles there was a correlation of industry sponsorship and positive study outcome.[92] A 2004
study of 1999–2001 RCTs published in leading medical and surgical journals determined that
industry-funded RCTs "are more likely to be associated with statistically significant pro-industry
findings."[93] These results have been mirrored in trials in surgery, where although industry funding
did not affect the rate of trial discontinuation it was however associated with a lower odds of
publication for completed trials.[94]

One possible reason for the pro-industry results in industry-
funded published RCTs is publication bias.[93] Other authors have cited the differing goals of
academic and industry sponsored research as contributing to the difference. Commercial sponsors
may be more focused on performing trials of drugs that have already shown promise in early stage
trials, and on replicating previous positive results to fulfill regulatory requirements for drug
approval.[95]
Ethics
If a disruptive innovation in medical technology is developed, it may be difficult to test this ethically
in an RCT if it becomes "obvious" that the control subjects have poorer outcomes—either due to
other foregoing testing, or within the initial phase of the RCT itself. Ethically it may be necessary to
abort the RCT prematurely, and getting ethics approval (and patient agreement) to withhold the
innovation from the control group in future RCT's may not be feasible.
Historical control trials (HCT) exploit the data of previous RCTs to reduce the sample size; however,
these approaches are controversial in the scientific community and must be handled with care.[96]
In social science
Due to the recent emergence of RCTs in social science, the use of RCTs in social sciences is a
contested issue. Some writers from a medical or health background have argued that existing
research in a range of social science disciplines lacks rigour, and should be improved by greater use
of randomized control trials.
Transport science
Researchers in transport science argue that public spending on programmes such as school travel
plans could not be justified unless their efficacy is demonstrated by randomized controlled trials.[97]
Graham-Rowe and colleagues[98] reviewed 77 evaluations of transport interventions found in the
literature, categorising them into 5 "quality levels". They concluded that most of the studies were of
low quality and advocated the use of randomized controlled trials wherever possible in future
transport research.
Dr. Steve Melia[99] took issue with these conclusions, arguing that claims about the advantages of
RCTs, in establishing causality and avoiding bias, have been exaggerated. He proposed the following
eight criteria for the use of RCTs in contexts where interventions must change human behaviour to
be effective:
The intervention:
1. Has not been applied to all members of a unique group of people (e.g. the population of a whole
country, all employees of a unique organisation etc.)
2. Is applied in a context or setting similar to that which applies to the control group
3. Can be isolated from other activities—and the purpose of the study is to assess this isolated
effect
4. Has a short timescale between its implementation and maturity of its effects
And the causal mechanisms:
1.
5. Are either known to the researchers, or else all possible alternatives can be tested
6. Do not involve significant feedback mechanisms between the intervention group and external
environments
7. Have a stable and predictable relationship to exogenous factors
8. Would act in the same way if the control group and intervention group were reversed
International development
RCTs are currently being used by a number of international development experts to measure the
impact of development interventions worldwide. Development economists at research organizations
including Abdul Latif Jameel Poverty Action Lab (J-PAL)[100][101][102] and Innovations for Poverty
Action[103] have used RCTs to measure the effectiveness of poverty, health, and education programs
in the developing world. While RCTs can be useful in policy evaluation, it is necessary to exercise
care in interpreting the results in social science settings. For example, interventions can
inadvertently induce socioeconomic and behavioral changes that can confound the relationships
(Bhargava, 2008).
For some development economists, the main benefit to using RCTs compared to other research
methods is that randomization guards against selection bias, a problem present in many current
studies of development policy. In one notable example of a cluster RCT in the field of development
economics, Olken (2007) randomized 608 villages in Indonesia in which roads were about to be built
into six groups (no audit vs. audit, and no invitations to accountability meetings vs. invitations to
accountability meetings vs. invitations to accountability meetings along with anonymous comment
forms).[104] After estimating "missing expenditures" (a measure of corruption), Olken concluded
that government audits were more effective than "increasing grassroots participation in monitoring"
in reducing corruption.[104] Overall, it is important in social sciences to account for the intended as
well as the unintended consequences of interventions for policy evaluations.
Criminology
A 2005 review found 83 randomized experiments in criminology published in 1982–2004,

compared with only 35 published in 1957–1981.[105] The authors classified the studies they found
into five categories: "policing", "prevention", "corrections", "court", and "community".[105] Focusing
only on offending behavior programs, Hollin (2008) argued that RCTs may be difficult to implement
(e.g., if an RCT required "passing sentences that would randomly assign offenders to programmes")
and therefore that experiments with quasi-experimental design are still necessary.[106]
Education
RCTs have been used in evaluating a number of educational interventions. Between 1980 and 2016,
over 1,000 reports of RCTs have been published.[107] For example, a 2009 study randomized 260
elementary school teachers' classrooms to receive or not receive a program of behavioral screening,
classroom intervention, and parent training, and then measured the behavioral and academic
performance of their students.[108] Another 2009 study randomized classrooms for 678 first-grade
children to receive a classroom-centered intervention, a parent-centered intervention, or no
intervention, and then followed their academic outcomes through age 19.[109]
Mock randomised controlled trials, or simulations using confectionery, can conducted in the
classroom to teach students and health professionals the principles of RCT design and critical
appraisal.[110]
Criticism
A 2017 review of the 10 most cited randomised controlled trials noted poor distribution of
background traits, difficulties with blinding, and discussed other assumptions and biases inherent in
randomised controlled trials. These include the "unique time period assessment bias", the
"background traits remain constant assumption", the "average treatment effects limitation", the
"simple treatment at the individual level limitation", the "all preconditions are fully met
assumption", the "quantitative variable limitation" and the "placebo only or conventional treatment
only limitation".[111]
See also
Drug development
Hypothesis testing
Impact evaluation
Jadad scale
Statistical inference
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Further reading
Berger, M. P. F.; Wong, W. K. (2009). An Introduction to Optimal Designs for Social and
Biomedical Research (http://eu.wiley.com/WileyCDA/WileyTitle/productCd-0470694505.html).
John Wiley & Sons. p. 346. ISBN 978-0-470-69450-3.
Bhargava Alok (2008). "Randomized controlled experiments in health and social sciences: Some
conceptual issues". Economics and Human Biology. 6 (2): 293–298.
doi:10.1016/j.ehb.2008.01.001 (https://doi.org/10.1016%2Fj.ehb.2008.01.001). PMID 18325858
Domanski MJ, McKinlay S. Successful randomized trials: a handbook for the 21st century.
Philadelphia: Lippincott Williams & Wilkins, 2009. ISBN 978-0-7817-7945-6.
Jadad AR, Enkin M. Randomized controlled trials: questions, answers, and musings. 2nd ed.
Malden, Mass.: Blackwell, 2007. ISBN 978-1-4051-3266-4.
Matthews JNS. Introduction to randomized controlled clinical trials. 2nd ed. Boca Raton, Fla.:
CRC Press, 2006. ISBN 1-58488-624-2.
Nezu AM, Nezu CM. Evidence-based outcome research: a practical guide to conducting
randomized controlled trials for psychosocial interventions. Oxford: Oxford University Press,
2008. ISBN 978-0-19-530463-3.
Solomon PL, Cavanaugh MM, Draine J. Randomized controlled trials: design and
implementation for community-based psychosocial interventions. New York: Oxford University
Press, 2009. ISBN 978-0-19-533319-0.
Torgerson DJ, Torgerson C. Designing randomised trials in health, education and the social
sciences: an introduction. Basingstoke, England, and New York: Palgrave Macmillan, 2008.
ISBN 978-0-230-53735-4.
External links
Bland M. Directory of randomisation software and services. (http://www-users.york.ac.uk/~mb55/
guide/randsery.htm) University of York, 2008 March 19.
Evans I, Thornton H, Chalmers I. Testing treatments: better research for better health care. (http
s://web.archive.org/web/20101225093331/http://www.jameslindlibrary.org/pdf/testing-treatments.
pdf) London: Pinter & Martin, 2010. ISBN 978-1-905177-35-6.
Gelband H. The impact of randomized clinical trials on health policy and medical practice:
background paper. (https://fas.org/ota/reports/8310.pdf) Washington, DC: U.S. Congress, Office
of Technology Assessment, 1983. (Report OTA-BP-H-22.)
REFLECT (Reporting guidElines For randomized controLled trials for livEstoCk and food safeTy)
Statement (http://reflect-statement.org/)
Wathen JK, Cook JD. Power and bias in adaptively randomized clinical trials. (http://www.mdand
erson.org/education-and-research/departments-programs-and-labs/departments-and-divisions/di
vision-of-quantitative-sciences/research/biostats-utmdabtr-002-06.pdf) M. D. Anderson Cancer
Center, University of Texas, 2006 July 12.
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4/21/2020 Randomized controlled trial - Wikipedia

Randomized controlled trial

In 2004, the International Committee of Medical Journal Editors (http://www.icmje.org/) (ICMJE)

Factorial – each participant is randomly assigned to a group that receives a particular

By outcome of interest (efﬁcacy vs. effectiveness)

RCTs can be classified as "explanatory" or "pragmatic."[36] Explanatory RCTs test efficacy in a

By hypothesis (superiority vs. noninferiority vs. equivalence)

An ideal randomization procedure would achieve the following goals:[41]

However, no single randomization procedure meets those goals in every circumstance, so

To balance group sizes in smaller RCTs, some form of "restricted" randomization is

Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio"

Covariate-adaptive randomization, of which one type is minimization: The probability of being

Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind";

using imputed data.[4]

Consort 2010 Statement: Extension to Cluster Randomised Trials[62]

Relative importance and observational studies

Interpretation of statistical results

Time and costs

Conﬂict of interest dangers

publication for completed trials.[94]

And the causal mechanisms:

A 2005 review found 83 randomized experiments in criminology published in 1982–2004,

15. According to Conniffe (1991, p. 87),

Ronald A. Fisher was "interested in application and in the popularization of statistical

16. Streptomycin in Tuberculosis Trials Committee (1948). "Streptomycin treatment of pulmonary

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This page was last edited on 13 April 2020, at 13:45 (UTC).

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